ABASAGLAR 100UI / ml injection for pre-filled pen medication leaflet

ABASAGLAR 100 units/mL KwikPen solution for injection in a pre-filled pen

ABASAGLAR 100 units/mL Tempo Pen solution for injection in a pre-filled pen

Each mL contains 100 units insulin glargine* (equivalent to 3.64 mg).

Each pen contains 3 mL of solution for injection, equivalent to 300 units.

* produced by recombinant DNA technology in Escherichia coli.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear, colourless solution.

Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.

ABASAGLAR contains insulin glargine, an insulin analogue and has a prolonged duration of action.

ABASAGLAR should be administered once daily at any time but at the same time each day.

The dose regimen (dose and timing) should be individually adjusted. In patients with type 2 diabetesmellitus, ABASAGLAR can also be given together with orally active antidiabetic medicinal products.

The potency of this medicinal product is stated in units. These units are exclusive to insulin glargineand are not the same as IU or the units used to express the potency of other insulin analogues (seesection 5.1).

In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulinrequirements.

In patients with renal impairment, insulin requirements may be diminished due to reduced insulinmetabolism.

In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacityfor gluconeogenesis and reduced insulin metabolism.

The safety and efficacy of insulin glargine have been established in adolescents and children aged2 years and older (see section 5.1). The dose regimen (dose and timing) should be individuallyadjusted.

The safety and efficacy of insulin glargine have not been established. No data are available.

When switching from a treatment regimen with an intermediate or long-acting insulin to a regimenwith ABASAGLAR, a change of the dose of the basal insulin may be required and the concomitantantidiabetic treatment may need to be adjusted (dose and timing of additional regular insulins or fast-acting insulin analogues or the dose of oral antidiabetic medicinal products).

To reduce the risk of nocturnal and early morning hypoglycaemia, patients who are changing theirbasal insulin regimen from a twice daily NPH insulin to a once daily regimen with ABASAGLARshould reduce their daily dose of basal insulin by 20-30 % during the first weeks of treatment.

ABASAGLAR and Toujeo (insulin glargine 300 units/ml) are not bioequivalent and are not directlyinterchangeable. To reduce the risk of hypoglycemia, patients who are changing their basal insulinregimen from an insulin regimen with once daily insulin glargine 300 units/ml to a once daily regimenwith ABASAGLAR should reduce their dose by approximately 20%.

During the first weeks the reduction should, at least partially, be compensated by an increase inmealtime insulin, after this period the regimen should be adjusted individually.

Close metabolic monitoring is recommended during the switch and in the initial weeks thereafter.

With improved metabolic control and resulting increase in insulin sensitivity a further adjustment indose regimen may become necessary. Dose adjustment may also be required, for example, if thepatient's weight or life-style changes, change of timing of insulin dose or other circumstances arise thatincrease susceptibility to hypoglycaemia or hyperglycaemia (see section 4.4).

Patients with high insulin doses because of antibodies to human insulin may experience an improvedinsulin response with ABASAGLAR.

ABASAGLAR is administered subcutaneously.

ABASAGLAR should not be administered intravenously. The prolonged duration of action of insulinglargine is dependent on its injection into subcutaneous tissue. Intravenous administration of the usualsubcutaneous dose could result in severe hypoglycaemia.

There are no clinically relevant differences in serum insulin or glucose levels after abdominal, deltoidor thigh administration of insulin glargine.

Injection sites should always be rotated within the same region in order to reduce the risk oflipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

ABASAGLAR must not be mixed with any other insulin or diluted. Mixing or diluting can change itstime/action profile and mixing can cause precipitation.

For further details on handling, see section 6.6.

Before using ABASAGLAR solution for injection in pre-filled pen, the instructions for use included inthe package leaflet must be read carefully (see section 6.6).

KwikPen

The KwikPen is registered in two presentations. One delivers 1 -60 units in steps of 1 unit in a singleinjection and the other delivers 1 - 80 units in steps of 1 unit in a single injection. The needed dose isdialled in units. The number of units is shown in the dose window of the pen.

Tempo Pen

The Tempo Pen delivers 1 - 80 units in steps of 1 unit in a single injection. The needed dose is dialledin units. The number of units is shown in the dose window of the pen.

The Tempo Pen can be used with the optional transfer module Tempo Smart Button (see section 6.6).

As with any insulin injection, when using the Tempo Pen, Smart Button and the mobile application,the patient should be instructed to check their blood sugar levels when considering or makingdecisions about another injection if they are unsure how much they have injected.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered medicinal product should be clearly recorded.

ABASAGLAR is not the insulin of choice for the treatment of diabetic ketoacidosis. Instead, regularinsulin administered intravenously is recommended in such cases.

In case of insufficient glucose control or a tendency to hyperglycaemic or hypoglycaemic episodes,the patient's adherence to the prescribed treatment regimen, injection sites and proper injectiontechnique and all other relevant factors must be reviewed before dose adjustment is considered.

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.),origin (animal, human, human insulin analogue) and/or method of manufacture may result in the needfor a change in dose.

The time of occurrence of hypoglycaemia depends on the action profile of the insulins used and may,therefore, change when the treatment regimen is changed. Due to more sustained basal insulin supplywith insulin glargine, less nocturnal but more early morning hypoglycaemia can be expected.

Particular caution should be exercised, and intensified blood glucose monitoring is advisable inpatients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patientswith significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk ofcardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferativeretinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis followinghypoglycaemia).

Patients should be aware of circumstances where warning symptoms of hypoglycaemia arediminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or beabsent in certain risk groups. These include patients:

- in whom glycaemic control is markedly improved,

- in whom hypoglycaemia develops gradually,

- who are elderly,

- after transfer from animal insulin to human insulin,

- in whom an autonomic neuropathy is present,

- with a long history of diabetes,

- suffering from a psychiatric illness,

- receiving concurrent treatment with certain other medicinal products (see section 4.5).

Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to thepatient's awareness of hypoglycaemia.

The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia.

If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent,unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.

Adherence of the patient to the dose and dietary regimen, correct insulin administration and awarenessof hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing thesusceptibility to hypoglycaemia require particularly close monitoring and may necessitate doseadjustment. These include:

- change in the injection area,

- improved insulin sensitivity (e.g., by removal of stress factors),

- unaccustomed, increased or prolonged physical activity,

- intercurrent illness (e.g. vomiting, diarrhoea),

- inadequate food intake,

- missed meals,

- alcohol consumption,

- certain uncompensated endocrine disorders, (e.g. in hypothyroidism and in anterior pituitary oradrenocortical insufficiency),

- concomitant treatment with certain other medicinal products.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia.

Blood glucose monitoring is recommended after the change in the injection site, and dose adjustmentof antidiabetic medications may be considered.

Intercurrent illness requires intensified metabolic monitoring. In many cases urine tests for ketones areindicated, and often it is necessary to adjust the insulin dose. The insulin requirement is oftenincreased. Patients with type 1 diabetes must continue to consume at least a small amount ofcarbohydrates on a regular basis, even if they are able to eat only little or no food, or are vomiting etc.and they must never omit insulin entirely.

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulinantibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- orhypoglycaemia (see section 5.1).

Medication errors have been reported in which other insulins, particularly short-acting insulins, havebeen accidentally administered instead of insulin glargine. Insulin label must always be checkedbefore each injection to avoid medication errors between ABASAGLAR pre-filled pen as well as otherinsulins.

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin,especially in patients with risk factors for development of cardiac heart failure. This should be kept inmind if treatment with the combination of pioglitazone and ABASAGLAR is considered. If thecombination is used, patients should be observed for signs and symptoms of heart failure, weight gainand oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Tempo Pen

The Tempo Pen contains a magnet (see section 6.5) that may interfere with the functions of animplantable electronic medical device, such as a pacemaker. The magnetic field extends toapproximately 1.5 cm.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially“sodium-free”.

A number of substances affect glucose metabolism and may require dose adjustment of insulinglargine.

Substances that may enhance the blood-glucose-lowering effect and increase susceptibility tohypoglycaemia include oral antidiabetic medicinal products, angiotensin converting enzyme (ACE)inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline,propoxyphene, salicylates, somatostatin anologues and sulphonamide antibiotics.

Substances that may reduce the blood-glucose-lowering effect include corticosteroids, danazol,diazoxide, diuretics, glucagon, isoniazid, oestrogens, progestogens, phenothiazine derivatives,somatropin, sympathomimetic medicinal products (e.g. epinephrine [adrenaline], salbutamol,terbutaline), thyroid hormones, atypical antipsychotic medicinal products (e.g. clozapine andolanzapine) and protease inhibitors.

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-glucoselowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followedby hyperglycaemia.

In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine,guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.

For insulin glargine no clinical data on exposed pregnancies from controlled clinical studies areavailable. A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicateno specific adverse effects of insulin glargine on pregnancy and no specific malformative norfeto/neonatal toxicity of insulin glargine.

Animal data do not indicate reproductive toxicity.

The use of ABASAGLAR may be considered during pregnancy, if clinically needed.

It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic controlthroughout pregnancy to prevent adverse outcomes associated with hyperglycaemia. Insulinrequirements may decrease during the first trimester and generally increase during the second andthird trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk ofhypoglycaemia). Careful monitoring of glucose control is essential.

It is unknown whether insulin glargine is excreted in human milk. No metabolic effects of ingestedinsulin glargine on the breast-fed newborn/infant are anticipated since insulin glargine as a peptide isdigested into amino acids in the human gastrointestinal tract.

Breast-feeding women may require adjustments in insulin dose and diet.

Animal studies do not indicate direct harmful effects with respect to fertility.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia orhyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk insituations where these abilities are of special importance (e.g. driving a car or using machines).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This isparticularly important in those who have reduced or absent awareness of the warning symptoms ofhypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it isadvisable to drive or operate machines in these circumstances.

Hypoglycaemia (very common), in general the most frequent adverse reaction of insulin therapy, mayoccur if the insulin dose is too high in relation to the insulin requirement (see section 4.4).

The following related adverse reactions from clinical trials are listed below as MedDRA preferredterm by system organ class and in order of decreasing incidence (very common: ≥1/10; common:≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA system Very Common Uncommon Rare Very Notorgan classes common rare known

Allergic reactions X

Hypoglycaemia X

Dysgeusia X

Visual impairment X

Retinopathy X

Lipohypertrophy X

Lipoatrophy X

Cutaneousamyloidosis X

Myalgia X

Injection site Xreactions

Oedema X

Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged orsevere hypoglycaemic episodes may be life-threatening. In many patients, the signs and symptoms ofneuroglycopenia are preceded by signs of adrenergic counter-regulation. Generally, the greater andmore rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulationand its symptoms.

Immediate-type allergic reactions to insulin are rare. Such reactions to insulin (including insulinglargine) or the excipients may, for example, be associated with generalised skin reactions, angio-oedema, bronchospasm, hypotension and shock, and may be life-threatening.

A marked change in glycaemic control may cause temporary visual impairment, due to temporaryalteration in the turgidity and refractive index of the lens.

Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

However, intensification of insulin therapy with abrupt improvement in glycaemic control may beassociated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy,particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result intransient amaurosis.

Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulinabsorption. Continuous rotation of the injection site within the given injection area may help to reduceor prevent these reactions (see section 4.4).

Injection site reactions include redness, pain, itching, hives, swelling, or inflammation. Most minorreactions to insulins at the injection site usually resolve in a few days to a few weeks.

Rarely, insulin may cause sodium retention and oedema particularly if previously poor metaboliccontrol is improved by intensified insulin therapy.

In general, the safety profile for children and adolescents (≤ 18 years of age) is similar to the safetyprofile for adults. The adverse reaction reports received from post marketing surveillance includedrelatively more frequent injection site reactions (injection site pain, injection site reaction) and skinreactions (rash, urticaria) in children and adolescents (≤ 18 years of age) than in adults. Clinical studysafety data are not available for children under 2 years.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Insulin overdose may lead to severe and sometimes long-term and life-threatening hypoglycaemia.

Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in doseof the medicinal product, meal patterns, or physical activity may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated withintramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrateintake and observation may be necessary because hypoglycaemia may recur after apparent clinicalrecovery.

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, long-acting.

ATC Code: A10AE04.

ABASAGLAR is a biosimilar medicinal product. Detailed information is available on the website ofthe European Medicines Agency http://www.ema.europa.eu.

Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH. It iscompletely soluble at the acidic pH of the ABASAGLAR injection solution (pH 4). After injectioninto the subcutaneous tissue, the acidic solution is neutralised leading to formation of micro-precipitates from which small amounts of insulin glargine are continuously released, providing asmooth, peakless, predictable concentration/time profile with a prolonged duration of action.

Insulin glargine is metabolised into 2 active metabolites M1 and M2 (see section 5.2).

In vitro studies indicate that the affinity of insulin glargine and its metabolites M1 and M2 for thehuman insulin receptor is similar to the one of human insulin.

IGF-1 receptor binding: The affinity of insulin glargine for the human IGF-1 receptor is approximately5 to 8-fold greater than that of human insulin (but approximately 70 to 80-fold lower than the one of

IGF-1), whereas M1 and M2 bind the IGF-1 receptor with slightly lower affinity compared to humaninsulin.

The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1diabetic patients was markedly lower than what would be required for a half maximal occupation ofthe IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated bythe IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate the mitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy, including in

ABASAGLAR therapy, are considerably lower than the pharmacological concentrations required toactivate the IGF-1 pathway.

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulinand its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially byskeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in theadipocyte, inhibits proteolysis and enhances protein synthesis.

In clinical pharmacology studies, intravenous insulin glargine and human insulin have been shown tobe equipotent when given at the same doses. As with all insulins, the time course of action of insulinglargine may be affected by physical activity and other variables.

In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of actionof subcutaneous insulin glargine was slower than with human NPH insulin, its effect profile wassmooth and peakless, and the duration of its effect was prolonged.

The following graph shows the results from a study in patients:

Figure 1: Activity profile in patients with type 1 diabetes____ insulin glargine

- ----- NPH insulin

Time (h) after s.c injection

End of observationperiod

* Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly meanvalues)

The longer duration of action of subcutaneous insulin glargine is directly related to its slower rate ofabsorption and supports once daily administration. The time course of action of insulin and insulinanalogues such as insulin glargine may vary considerably in different individuals or within the sameindividual

In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses were similarafter intravenous insulin glargine and human insulin both in healthy volunteers and patients withtype 1 diabetes.

In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observedwith the same frequency in both NPH-insulin and insulin glargine treatment groups.

Effects of insulin glargine (once daily) on diabetic retinopathy were evaluated in an open-label 5 year

NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in which progression ofretinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale wasinvestigated by fundus photography. No significant difference was seen in the progression of diabeticretinopathy when insulin glargine was compared to NPH insulin.

The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter,randomised, 2x2 factorial design study conducted in 12,537 participants at high cardiovascular (CV)risk with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) ortype 2 diabetes mellitus treated with ≤1 antidiabetic oral agent (88% of participants). Participants wererandomised (1:1) to receive insulin glargine (n=6,264), titrated to reach FPG ≤95 mg/dL (5.3 mM), orstandard care (n=6,273).

The first co-primary efficacy outcome was the time to the first occurrence of CV death, nonfatalmyocardial infarction (MI), or nonfatal stroke, and the second co-primary efficacy outcome was thetime to the first occurrence of any of the first co-primary events, or revascularisation procedure(coronary, carotid, or peripheral), or hospitalisation for heart failure.

Secondary endpoints included all-cause mortality and a composite microvascular outcome.

Glucose Utilization

Rate* (mg/kg/min)

Insulin glargine did not alter the relative risk for CV disease and CV mortality when compared tostandard of care. There were no differences between insulin glargine and standard care for the two co-primary outcomes; for any component endpoint comprising these outcomes; for all-cause mortality; orfor the composite microvascular outcome.

Mean dose of insulin glargine by study end was 0.42 U/kg. At baseline, participants had a median

HbA1c value of 6.4% and median on-treatment HbA1c values ranged from 5.9 to 6.4% in the insulinglargine group, and 6.2% to 6.6% in the standard care group throughout the duration of follow-up. Therates of severe hypoglycaemia (affected participants per 100 participant years of exposure) were 1.05for insulin glargine and 0.30 for standard care group and the rates of confirmed non-severehypoglycaemia were 7.71 for insulin glargine and 2.44 for standard care group. Over the course of this6-year study, 42% of the insulin glargine group did not experience any hypoglycaemia.

At the last on-treatment visit, there was a mean increase in body weight from baseline of 1.4 kg in theinsulin glargine group and a mean decrease of 0.8 kg in the standard care group.

In a randomised, controlled clinical study, paediatric patients (age range 6 to 15 years) with type 1diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular humaninsulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPHhuman insulin was administered once or twice daily. Similar effects on glycohaemoglobin and theincidence of symptomatic hypoglycaemia were observed in both treatment groups, however fastingplasma glucose decreased more from baseline in the insulin glargine group than in the NPH group.

There was less severe hypoglycaemia in the insulin glargine group as well. One hundred forty three ofthe patients treated with insulin glargine in this study continued treatment with insulin glargine in anuncontrolled extension study with mean duration of follow-up of 2 years. No new safety signals wereseen during this extended treatment with insulin glargine.

A crossover study comparing insulin glargine plus lispro insulin to NPH plus regular human insulin(each treatment administered for 16 weeks in random order) in 26 adolescent type 1 diabetic patientsaged 12 to 18 years was also performed. As in the paediatric study described above, fasting plasmaglucose reduction from baseline was greater in the insulin glargine group than in the NPH group.

HbA1c changes from baseline were similar between treatment groups; however blood glucose valuesrecorded overnight were significantly higher in the insulin glargine/ lispro group than the NPH/regulargroup, with a mean nadir of 5.4 mM vs. 4.1 mM. Correspondingly, the incidences of nocturnalhypoglycaemia were 32 % in the insulin glargine/lispro group vs. 52 % in the NPH/regular group.

A 24-week parallel group study was conducted in 125 children with type 1 diabetes mellitus aged 2 to6 years, comparing insulin glargine given once daily in the morning to NPH insulin given once ortwice daily as basal insulin. Both groups received bolus insulin before meals. The primary aim ofdemonstrating non-inferiority of insulin glargine to NPH in all hypoglycaemia was not met and therewas a trend to an increase of hypoglycaemic events with insulin glargine [insulin glargine: NPH rateratio (95% CI) = 1.18 (0.97-1.44)]. Glycohaemoglobin and glucose variabilities were comparable inboth treatment groups. No new safety signals were observed in this trial.

In healthy subjects and diabetic patients, insulin serum concentrations indicated a slower and muchmore prolonged absorption and showed a lack of a peak after subcutaneous injection of insulinglargine in comparison to human NPH insulin. Concentrations were thus consistent with the timeprofile of the pharmacodynamic activity of insulin glargine. Figure 1 above shows the activity profilesover time of insulin glargine and NPH insulin.

Insulin glargine injected once daily will reach steady state levels in 2-4 days after the first dose.

After subcutaneous injection in diabetic patients, insulin glargine is rapidly metabolised at thecarboxyl terminus of the Beta chain with formation of two active metabolites M1 (21A-Gly-insulin)and M2 (21A-Gly-des-30B-Thr-insulin). In plasma, the principal circulating compound is themetabolite M1. The exposure to M1 increases with the administered dose of insulin glargine.

The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneousinjection with insulin glargine is principally based on exposure to M1. Insulin glargine and themetabolite M2 were not detectable in the vast majority of subjects and, when they were detectabletheir concentration was independent of the administered dose of insulin glargine.

When given intravenously the elimination half-life of insulin glargine and human insulin werecomparable.

In clinical studies, subgroup analyses based on age and gender did not indicate any difference in safetyand efficacy in insulin glargine-treated patients compared to the entire study population.

Pharmacokinetics in children aged 2 to less than 6 years with type 1 diabetes mellitus was assessed inone clinical study (see section 5.1). Plasma trough levels of insulin glargine and its main M1 and M2metabolites were measured in children treated with insulin glargine, revealing plasma concentrationpatterns similar to adults, and providing no evidence for accumulation of insulin glargine or itsmetabolites with chronic dosing.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Zinc oxide

Metacresol

Glycerol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products.

2 years.

The medicinal product may be stored for a maximum of 28 days up to 30°C and away from direct heator direct light. Pens in use must not be stored in the refrigerator.

The pen cap must be put back on the pen after each injection in order to protect from light.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Do not store ABASAGLAR next to the freezer compartment or a freezer pack.

Keep the pre-filled pen in the outer carton in order to protect from light.

For storage conditions after first opening of this medicinal product, see section 6.3.

KwikPen3 mL solution in a cartridge (type 1 colourless glass) with a plunger (halobutyl rubber) and a disc seal(laminate of polyisoprene and halobutyl rubber) with aluminium seal.

The cartridge is sealed in a disposable pen injector.

Packs of 5 pre-filled pens and multipacks containing 10 (2 packs of 5) pre-filled pens.

Tempo Pen3 mL solution in a cartridge (type 1 colourless glass) with a plunger (halobutyl rubber) and a disc seal(laminate of polyisoprene and halobutyl rubber) with aluminium seal. The cartridge is sealed in adisposable pen injector. The Tempo Pen contains a magnet (see section 4.4).

Packs of 5 pre-filled pens and multipacks containing 10 (2 packs of 5) pre-filled pens.

Not all pack sizes may be marketed.

Needles are not included in the pack.

ABASAGLAR must not be mixed with any other insulin or medicinal products or diluted. Mixing ordiluting can change its time/action profile and mixing can cause precipitation.

Inspect the cartridge before use. It must only be used if the solution is clear, colourless, with no solidparticles visible, and if it is of water-like consistency. Since ABASAGLAR is a solution, it does notrequire re-suspension before use.

ABASAGLAR must not be mixed with any other insulin or diluted. Mixing or diluting can change itstime/action profile and mixing can cause precipitation.

Empty pens must never be reused and must be properly discarded.

To prevent the possible transmission of disease, each pen must be used by one patient only.

Insulin label must always be checked before each injection to avoid medication errors between insulinglargine and other insulins (see section 4.4).

The patient should be advised to read the instructions for use included in the package leaflet carefullybefore using ABASAGLAR solution for injection in pre-filled pen.

Tempo Pen

The Tempo Pen is designed to work with the Tempo Smart Button. The Tempo Smart Button is anoptional product that can be attached to the Tempo Pen dose knob and aids in transmitting Abasaglardose information from the Tempo Pen to a compatible mobile application. The Tempo Pen injectsinsulin with or without the Tempo Smart Button attached. To transmit data to the mobile application,follow the instructions provided with the Tempo Smart Button and the instructions with the mobileapplication.

Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands

EU/1/14/944/007

EU/1/14/944/008

EU/1/14/944/012

EU/1/14/944/013

EU/1/14/944/014

EU/1/14/944/015

Date of first authorisation: 9 September 2014

Date of latest renewal: 25 July 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu